Strict blood pressure control fails to halt the progression of hypertensive nephrosclerosis (HN) in African Americans, suggesting that factors in addition to high blood pressure are involved in disease causation. This application proposes to determine the natural history of MYH9-associated HN in African Americans, as MYH9 accounts for 70% of all non- diabetic cases of end-stage renal disease (ESRD) in this ethnic group. All individuals who are homozygous for MYH9 risk alleles do not develop kidney disease, demonstrating that MYH9 gene-environment and MYH9 gene-gene interactions contribute to kidney disease risk. This application proposes to recruit and longitudinally evaluate African American individuals who are at high risk for developing HN by virtue of having a first degree relative with hypertension-associated ESRD. The impact of lifestyle and environmental factors causing kidney disease will be evaluated as potential second hits for MYH9-associated nephropathy. A repository of biologic specimens will be collected from participants and we will test for association between development of HN and exposure to latent viral infections potentially predisposing to kidney disease. The rationale for this approach is based on the strong association of MYH9 risk haplotypes with Human Immunodeficiency Virus (HIV)-associated nephropathy (HIVAN) in African Americans. HIVAN and HN may both present as focal segmental glomerulosclerosis. The role of MYH9 gene-gene interaction between MYH9 and other HN susceptibility genes would be explored in concert with our ongoing R01 DK070941. The major components of this project are: (1) recruitment of 1,200 unrelated African American subjects at high risk for HN based upon family history of H-ESRD, with phenotyping for the presence of hypertension, kidney disease and kidney disease-risk factors; (2) longitudinal follow-up to determine the association of MYH9 gene polymorphisms with cross-sectional and longitudinal measures of blood pressure, albuminuria, serum cystatin C and creatinine concentrations, and estimated glomerular filtration rates in members of the cohort; and (3) creation of a repository of biologic specimens to detect environmental factors that may trigger MYH9-associated nephropathy in genetically susceptible individuals. We will test for evidence of latent viral infections associated with HN (MYH9 gene-environment interactions). PUBLIC HEALTH RELEVANCE: From this study we will be able to identify relatives with and without the MYH9 nephropathy genotype and investigate the role of environmental and genetic factors on the development and progression of kidney disease. We expect that this study will aid in predicting risk for progressing to ESRD in families with MYH9-nephropathy. While there may be no immediate benefit to ESRD patients, the study will help anticipate which MYH9 risk homozygotes need to be closely monitored for development of nephropathy. This will benefit individuals at risk who could benefit from therapeutic intervention to alleviate disease at an earlier stage. The anticipated benefits to the population at large outweigh the minimal risk involved in the study.